Repression of GRIM19 expression potentiates cisplatin chemoresistance in advanced bladder cancer cells via disrupting ubiquitination-mediated Bcl-xL degradation
Abstract
The mainstay of treatment for advanced bladder cancer (BC) is cisplatin (CDDP)-based systematic chemotherapy. However, acquired chemoresistance induced by as yet unidentified mechanisms is encountered frequently and often results in treatment failure and disease progression. The present study was designed to elucidate the expression and potential role of the gene associated with retinoid-interferon-induced mortality-19 (GRIM19) in the pathogenesis of CDDP resistance in BC. RT-qPCR and immunoblotting were employed to evaluate the expression profile of GRIM19 in clinical BC samples and in different BC cells. Using cell viability assay, apoptotic ELISA, xenografts mouse model, and Transwell assay, the effects of GRIM19 inhibition or GRIM19 overexpression on CDDP resistance were determined in different BC cells. Lastly, using co-immunoprecipitation, we provided the molecular evidence for the interaction between GRIM19 and Bcl-xL. Expression levels of GRIM19 were significantly down-regulated in recurrent BC specimens, and in experimentally induced CDDP-resistant BC cells. Functionally, overexpression of the exogenous GRIM19 potentiated CDDP sensitivity and suppressed the survival and invasion of BC cells in the presence of CDDP chal...Continue Reading
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